Antimicrobial imidazolium derivatives

Abstract

Compounds of the formula <IMAGE> I wherein the various substituents are defined hereinbelow and the pharmaceutically acceptable acid addition salts thereof, possess pharmacological properties. In particular, they possess antibacterial, antimycotic, protozoacidal and/or anthelmintic properties.

What is claimed is: 
     
       1. A compound of the formula ##STR21## wherein Q is a mono or bicyclic carbocyclic aromatic group with two free valencies, or a mono or biheterocyclic aromatic group with two free valencies; --NH 1  R 2  is a basic amino group wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or a saturated or unsaturated lower hydrocarbon group or R 1  or R 2  together with the nitrogen atom is a substituted or unsubstituted 5 to 7 membered saturated N-heterocycle with the substituents selected from the group consisting of one or two lower alkyl groups and which can contain as a ring member in place of one methylene group an oxygen or sulphur atom or the group >SO, >SO 2 , >CO, >CH--Rd, or >N--Re wherein Rd is hydroxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, mono or di(lower alkyl), carbamoyl or a saturated or partially unsaturated lower hydrocarbon group which may contain one or two oxygen atoms in ethereal and/or alcoholic form   R 3  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl or lower haloalkyl;   R 4  is a basic amino group as defined above or the group --N═CRc--Ra, --(NH) n  --CH(Rc)--Ra 1 , --NH--CO--Rb, --CH 2  --CO--Rb or --N═CR 6  --Q--NR'R 2  ;   R 5  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxy alkyl, lower haloalkyl, a mono- or bicyclic carbocyclic aromatic group or is together with the atoms in the 4- and 5-positions of the imidazole ring a benzene ring,   R 6  is hydrogen or lower alkyl;   Ra is a mono- or bicyclic carbocyclic aromatic group, a mono- or biheterocyclic aromatic group; or a basic amino group as defined above;   Ra 1  is a mono- or bicyclic carbocyclic aromatic group or a mono- or biheterocyclic aromatic group;   Rb is hydrogen, Q 1 , --OQ 1 , or a mono- or bicyclic carbocyclic aromatic group, a mono- or biheterocyclic aromatic group, or a basic amino group as defined above which may be attached via a lower alkyl group;   Rc is hydrogen or lower alkyl;   n is 0 or 1;   the dotted line is an additional double bond;   Q 1  is a saturated or partially unsaturated lower hydrocarbon which may contain one or two oxygen atoms in ethereal and/or alcoholic form;   Y -  is a pharmaceutically acceptable anion;   with the proviso that R 3  is other than hydrogen or methyl when R 4  is --N═CH--Q--NR 1  R 2 ,   R 1  and R 2  are each methyl,   R 5  and R 6  are each hydrogen,   Q is 1,4-phenylene and Y is chlorine   or a pharmaceutically acceptable acid addition salt thereof.   
     
     
       2. The compound of claim 1 wherein R 3  is hydrogen or lower alkyl; R 4  is --N═CH--Ra, --(NH) n  --CH 2  Ra 1 , --NH--CO--Rb or --CH 2  --CO--Rb; and R 5  and R 6  are ach hydrogen. 
     
     
       3. The compound of claim 1, wherein R 4  is --N═CR 6  --Q--NR 1  R 2 . 
     
     
       4. The compound of claim 3 wherein Q is a substituted or unsubstituted 1,4-phenylene or 1,4-naphthylene, wherein the substituents are selected from the group consisting of one or two lower alkyl lower alkoxy. 
     
     
       5. The compound of claim 4, wherein Q is 1,4-phenylene. 
     
     
       6. The compound of claim 1, wherein R 1  and R 2  are each hydrogen or lower alkyl or together with the nitrogen atom are a substituted or unsubstituted 4-morpholinyl, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower alkoxycarbonyl)-1-piperazinyl or 1-pyrrolidinyl with the substituents selected from the group consisting of one or two lower alkyl. 
     
     
       7. The compound of claim 6, wherein R 1  and R 2  are lower alkyl. 
     
     
       8. The compound of claim 1, wherein R 3  is lower alkyl. 
     
     
       9. The compound of claim 1, wherein R 4  is --N═CRc--Ra or --CH 2  --CO--Rb; Ra is a substituted or unsubstituted phenyl with the substituents selected from the group consisting of one or two lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, halogen, trifluoromethyl, hydroxy, nitro or cyano; and Rb is a substituted or unsubstituted lower alkyl, lower alkoxy or phenyl with the substituents selected from the group consisting of one or two lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, halogen, trifluoromethyl, hydroxy, nitro or cyano. 
     
     
       10. The compound of claim 1, wherein R 5  is hydrogen. 
     
     
       11. The compound of claim 1, wherein R 6  and Rc are hydrogen. 
     
     
       12. The compound of claim 1 which is 3-[p-(Chlorobenzylidene)amino]-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride. 
     
     
       13. The compound of claim 1 which is 3-[p-(Dimethylamino)phenacyl]-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride. 
     
     
       14. The compound of claim 1 which is 1,3-Bis[(p-(dimethylamino)benzylidene]amino-2-ethylimidazolium chloride. 
     
     
       15. The compound of claim 1 which is 1-[[p-(Dimethylamino)benzylidene]amino]-2-ethyl-3-[(p-nitrobenzylidene)amino]imidazolium chloride. 
     
     
       16. The compound of claim 1 which is 1,3-Bis[[p-(dimethylamino)benzylidene]amino]-2-propylimidazolium chloride. 
     
     
       17. A compound of the formula ##STR22## wherein Q is substituted or unsubstituted 1,4-phenylene or 1,4-naphthylene with the substituents selected from the group consisting of one or two lower alkyl or lower alkoxy; R 1  and R 2  are each independently hydrogen or lower alkyl or R 1  and R 2  taken together with the adjacent nitrogen atom are substituted or unsubstituted 4-morpholinyl, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower alkoxy carbonyl)-1-piperazinyl or 1-pyrrolidinyl with the substituents selected from the group consisting of one or two lower alkyl groups; R 3  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl or lower haloalkyl; R 5  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkyl, a mono- or bicyclic carbocyclic aromatic group or is together with the atoms in the 4- and 5-positions at the imidazole ring a benzene ring; R 6  is hydrogen or lower alkyl; the dotted line is an additional double bond; Y -  is a pharmaceutically acceptable anion, provided that R 3  may not equal hydrogen or methyl when Q is equal to 1,4-phenylene, R 1  and R 2  are equal to methyl, R 5  and R 6  are equal to hydrogen and Y -  is equal to Cl; or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       18. The compound of claim 17 wherein Q is 1,4-phenylene. 
     
     
       19. The compound of claim 18 wherein R 1  and R 2  are lower alkyl. 
     
     
       20. The compound of claim 19 wherein R 3  is lower alkyl; R 5  is hydrogen; and R 6  is hydrogen. 
     
     
       21. The compound of claim 17 which is selected from the group consisting of 1,3-Bis[[p-(dimethylamino)-benzylidene]amino]-2-ethylimidazolium chloride and 1,3-Bis[[p-(dimethylamino)benzylidene]amino]-2-propylimidazolium chloride. 
     
     
       22. An antibacterial, antimycotic, antiprotozoacidal, or antihelminthic composition containing a pharmacologically effective amount of an imidazolium compound or a pharmaceutically acceptable acid addition salt thereof and an inert carrier material wherein said compound has the formula ##STR23## wherein Q is a mono or bicyclic carbocyclic aromatic group with two free valencies, or a mono or biheterocyclic aromatic group; --NR 1  R 2  is a basic amino group wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or a saturated or unsaturated lower hydrocarbon group or R 1  and R 2  together with the nitrogen atom is a substituted or unsubstituted 5 to 7 membered saturated N-heterocycle with the substituents selected from the group consisting of one or two lower alkyl groups and which can contain as a ring member in place of one methylene group an oxygen or sulphur atom or the group >SO, >SO 2 , >CO, >CH--Rd, or >N--Re wherein Rd is hydroxy, lower alkanoyl, lower alkoxycarbonyl, carbamoyl, mono or di(lower alkyl) carbamoyl or a saturated or partially unsaturated lower hydrocarbon group which may contain one or two oxygen atoms in ethereal and/or alcoholic form; R 3  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl or lower haloalkyl; R 4  is a basic amino group as defined above or the group --N═CRc--Ra, --(NH) n  --CH(Rc)--Ra 1 , --NH--CO--Rb, --CH 2  --CO--Rb or --N═CR 6  --Q--NR 1  R 2  ; R 5  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxy alkyl, lower haloalkyl, a monobicyclic carbocyclic aromatic group or is together with the atoms in the 4- and 5-positions at the imidazole ring a benzene ring; R 6  is hydrogen or lower alkyl; Ra is a mono- or bicyclic carbocyclic aromatic group, a mono- or biheterocyclic aromatic group or a basic amino group as defined above; Ra 1  is a mono- or bicyclic carbocyclic aromatic group or; Rb is hydrogen, --Q', --OQ' or a mono- or bicyclic carbocyclic aromatic group, a mono- or biheterocyclic aromatic group, or basic amino group defined as above which may be attached via a lower alkyl group; Rc is hydrogen or lower alkyl; n is 0 or 1; the dotted line is an additional double bond; Q' is a saturated or partially unsaturated lower hydrocarbon which may contain one or two oxygen atoms in ethereal and/or alcoholic form; and the symbol Y -  is a pharmaceutically acceptable anion. 
     
     
       23. The composition of claim 22, wherein R 3  is hydrogen or lower alkyl; R 4  is --N═CH--Ra, --(NH) n  --CH 2  --Ra', --NH--CO--Rb or --CH 2  --CO--Rb; and R 5  and R 6  are each hydrogen. 
     
     
       24. The composition of claim 22, wherein R 4  is --N═CR 6  --Q--NR 1  R 2 . 
     
     
       25. The composition of claim 24, wherein Q is substituted or unsubstituted 1,4-phenylene or 1,4-naphthylene, wherein the substituents are selected from the group consisting of one or two lower alkyl and lower alkoxy. 
     
     
       26. The composition of claim 25, wherein Q is 1,4-phenylene. 
     
     
       27. The composition of claim 22, wherein R 1  and R 2  are each hydrogen or lower alkyl or together with the nitrogen atom are substituted or unsubstituted 4-morpholinyl, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower alkoxycarbonyl)-1-piperazinyl or 1-pyrrolidinyl with the substituents selected from the group consisting of one or two lower alkyl groups. 
     
     
       28. The composition of claim 27, wherein R 1  and R 2  are each lower alkyl. 
     
     
       29. The composition of claim 22, wherein R 3  is lower alkyl. 
     
     
       30. The composition of claim 22, wherein R 4  is --N═CRc--Ra or --CH 2  --CO--Rb; Ra is substituted or unsubstituted phenyl with the substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, halogen, trifluoromethyl, hydroxy, nitro and cyano; and Rb is substituted or unsubstituted lower alkyl, lower alkoxy or phenyl with the substituents selected from the group consisting of one or two lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, halogen, trifluoromethyl, hydroxy, nitro and cyano. 
     
     
       31. The composition of claim 22, wherein R 5  is hydrogen. 
     
     
       32. The composition of claim 22, wherein R 6  and Rc are hydrogen. 
     
     
       33. The composition of claim 22 wherein said compound is 3-[p-(Chlorobenzylidene)amino]-1-[[p-(dimethylamino)-benzylidene]amino]-2-ethylimidazolium chloride. 
     
     
       34. The composition of claim 22 wherein said compound is 3-[p-(Dimethylamino)phenacyl]-1-[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride. 
     
     
       35. The composition of claim 22 wherein said compound is 1,3-Bis[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride. 
     
     
       36. The composition of claim 22 wherein said compound is 1-[[P-(Dimethylamino)benzylidene]amino]-2-ethyl-3-[(p-nitrobenzylidene)amino]imidazolium chloride. 
     
     
       37. The composition of claim 22 wherein said compound is 1,3-Bis[[p-(dimethylamino)benzylidene]amino]-2-propylimidazolium chloride. 
     
     
       38. An antibacterial, antimycotic, antiprotozoacidal or antihelminthic composition comprising a pharmcologically effective amount of an imidazolium compound, or a pharmaceutical acceptable acid addition salt thereof, and an inert carrier material wherein said compound has the formula ##STR24## wherein Q is substituted or unsubstituted 1,4-phenylene or 1,4-naphthylene wherein the substituents are selected from the group consisting of one or two lower alkyl or lower alkoxy; R 1  and R 2  are each independently hydrogen or lower alkyl or taken together with the adjacent nitrogen atom are substituted or unsubstituted 4-morpholinyl, 1-piperazinyl, 4-(lower alkyl)-1-piperazinyl, 4-(lower alkoxy carbonyl)-1-piperazinyl, or 1-pyrrolidinyl with the substituents selected from the group consisting of one or two alkyl groups; R 3  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl or lower haloalkyl; R 5  is hydrogen, lower alkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkyl, a mono- or bicyclic carbocyclic aromatic group or is together with the atoms in the 4- and 5-positions of imidazole ring a benzene ring; R 6  is hydrogen or lower alkyl; the dotted line signifies an additional double bond; Y -  is a pharmaceutically acceptable anion. 
     
     
       39. The composition of claim 38 wherein Q is 1,4-phenylene. 
     
     
       40. The composition of claim 39 wherein R 1  and R 2  are lower alkyl. 
     
     
       41. The composition of claim 40 wherein R 3  is lower alkyl; R 5  is hydrogen; and R 6  is hydrogen. 
     
     
       42. The composition of claim 38 wherein said compound is selected from the group consisting of 1,3-Bis[[p-(dimethylamino)benzylidene]amino]-imidazolium chloride, 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride, 1,3-Bis[[p-(dimethylamino)-benzylidene]amino]-2-ethylimidazolium chloride, and 1,3-Bis[[p-(dimethylamino)benzylidene]amino]-2-propylimidazolium chloride.